BREAST CANCER MORTALITY DECLINING IN EU

Breast cancer mortality has declined across Europe, but there are still notable differences between countries, according to new data presented at the 9th European Breast Cancer Conference in Glasgow, United Kingdom.

Researchers reported that the death rate from breast cancer had decreased in 31 European countries from 1989 to 2010. But the variations observed in individual countries cannot be explained simply by the resources devoted to cancer care.

The average annual change was –1.5% for all countries, and it appears that between 2003 and 2010, the average annual change was –1.9%. Decreases in breast cancer mortality have accelerated during the last decade, note the authors, and at present there is no sign that decreases will stabilize in coming years.

But while the decrease in breast cancer mortality in 2010 was greatest in countries with the highest death rates in the late 1980s, there were notable exceptions, said study author Philippe Autier, MD, PhD, from the Strathclyde Institute for Global Public Health at iPRI, Lyon, France.

The French Paradox

France, perhaps, represents the biggest conundrum.

"In 1987-9, rates in Italy, France and Norway were 29.7%, 28% and 27.4% respectively, but the respective declines in mortality rates 22 years later were 26.4%, 15.8%, and 34.5%, and of all European countries, the lowest mortality reductions in women aged less than 50 were also to be found in France," he said in a statement. "Given that France devotes substantial resources to cancer care and that Frenchwomen have access to the best treatment, there is something going on here that we don't understand and that needs urgent investigation."

In a 2010 paper published in the BMJ, Dr. Autier and colleagues had first noted the seeming "French paradox." (BMJ. 2010;341:c3620). At that time, the authors reported that "some countries, such as France and Sweden, have mobilized large resources on screening and acquisition of cancer drugs but have shown little change in breast cancer mortality."

At that time, the reaction of the French National Cancer Institute (INCA) was to say that the health benefits of the cancer plan were going to become apparent in the next few years, Dr. Autier said during a press briefing. "Four years later, positive changes announced by the INCA are still awaited."

France has a highly organized screening program and the highest spending on cancer drugs in Europe, and it is at the forefront of the use of new treatments. However, it has experienced a modest decrease in breast cancer mortality.

The same holds for Sweden, which has devoted considerable resources to screening yet has shown little change in mortality rates, Dr. Autier noted. There was a 23.7% decline in mortality between 1989 and 2010, but during that same time period, breast cancer mortality dropped by 34.3% in neighboring Norway—which introduced a nationwide screening program 15 years after Sweden did.

That said, considerable declines in breast cancer deaths have been observed in countries where major screening programs did not really get off the ground until after 2000 (Norway, Belgium, Switzerland, and Austria). These reductions were similar to or greater than those in countries that implemented screening at the end of the 1980s, such as Sweden, The Netherlands, the United Kingdom, and Finland.

"These are some of the many factors that continue to puzzle us, and we need to put considerable effort into finding out why these differences exist," Dr. Autier commented.

Screening Not Detecting Advanced Cancers

Another interesting observation was seen in the countries that formerly had the highest and lowest death rates.

In 1987–1989, breast cancer mortality rates were highest in England and Wales (41.9 per 100,000) and lowest in Romania (20 per 100,000). But in 2008–2010 these rates were 25.4 in England and Wales and 22 in Romania. This translates to a 40.8% decrease in mortality in England an 11.4% increase in Romania.

Many possible reasons may explain the differences observed between countries. Dr. Autier pointed to screening, which has played an important role in detecting tumors at smaller sizes. But trends in the incidence of advanced breast cancer have remained stable, suggesting that screening has not succeeded in detecting potentially life-threatening cancers at an earlier stage. In addition, the number of metastatic cancers present at diagnosis has also not declined.

"Hence these reductions in size simply represent the increasing incidence of small, early, non–life-threatening cancers that are detected by screening and which give an overall impression that things are getting better in terms of outcomes," said Dr. Autier. "As a result, we can say that decreased numbers of breast cancer deaths are largely due to improved treatments, not to screening."

Ongoing Challenge to Find Answers

Their report also showed that women under age 50 had the greatest reduction in mortality (from –71.3% to –21.4%). In contrast, the smallest decreases were observed in women 70 years and older (from –29.5% to 81.5%). Breast cancer mortality among older women is also continuing to rise in several countries, particularly those in central and Eastern Europe, a finding that can be attributed primarily to undertreatment.

"These findings are an important contribution to the ongoing challenge of understanding which strategies should be implemented to improve survival from breast cancer," said Hilary Dobson, MD, chair of 9th European Breast Cancer Conference's national organizing committee, clinical lead of the West of Scotland Breast Screening Service, and the lead clinician of the West of Scotland Cancer Advisory Network.

"Comparison among countries reveals a picture of variation and real complexity when considering factors such as population screening or access to cancer drugs," she said in a statement. "As no single factor emerges as an answer, continuing scrutiny on this scale and analysis is vital."

9th European Breast Cancer Conference. Presented March 28, 2014. Abstract O-410.

ANASTRAZOLE FOR HIGH RISK POSTMENOPAUSAL WOMEN

In the phase III IBIS-II trial, reported in The Lancet, Cuzick et al found that aromatase inhibitor therapy with anastrozole reduced risk of breast cancer in postmenopausal women at high risk of the disease.

Study Details

In this double-blind trial, 3,864 postmenopausal women aged 40 to 70 years from 18 countries were randomly assigned between February 2003 and January 2012 to receive 1 mg of anastrozole (n = 1,920) or placebo (n = 1,944) daily for 5 years. Estimated risk for breast cancer had to be at least 2 times higher than that in the general population for women aged 45 to 60 years, at least 1.5 times higher in those aged 60 to 70 years, and 4 times higher in those aged 40 to 44 years; if patients did not meet eligibility criteria, Tyrer-Cuzick 10-year risk had to be > 5%. The primary endpoint was histologically confirmed breast cancer, consisting of invasive cancers or noninvasive ductal carcinoma in situ.

Women in the anastrozole group and placebo group were well balanced for age (median, 59.5 and 59 years), age at menarche (median, 13 years in both), age at first child birth (median, 24 years in both), body mass index (eg, < 25 kg/m2 in 30% and 29%, 25–30 kg/m2in 36% and 38%), previous use of hormone replacement therapy (47% in both, 7% and 8% within previous 12 months), hysterectomy (33% and 34%), at least two first- or second-degree relatives with breast or ovarian cancer (50% and 48%), at least one first-degree relative with breast cancer at age ≤50 years (35% and 34%), at least one first-degree relative with bilateral breast cancer (9% and 7%), lobular carcinoma in situ or atypical hyperplasia (8% and 10%), estrogen receptor–positive ductal carcinoma in situ treated with mastectomy within 6 months (8% and 9%), and 10-year Tyrer-Cuzick risk (median, 7.6% and 7.8%).

Bisphosphonates were used during the trial by 17% of patients in the anastrozole group and 15% in the placebo group.

Risk Reduction

After a median follow-up of 5 years, 40 women in the anastrozole group (2%) and 85 in the placebo group (4%) had developed breast cancer (hazard ratio [HR] = 0.47, P < .0001). Anastrozole was associated with significantly reduced risk of all invasive cancers (2% vs 3%, HR  = 0.50, P = .001), invasive estrogen receptor–positive cancers (1% vs 2%, HR  = 0.42, P = .001), and ductal carcinoma in situ (< 1% vs 1%, HR = 0.30, P = .009), with no difference between groups in risk for invasive estrogen receptor–negative cancers (1% vs 1%, HR  = 0.79, P = .538). The predicted cumulative incidence of all breast cancers at 7 years was 5.6% vs 2.8%.

The frequency of cancers other than breast cancer was significantly lower in the anastrozole group (2% vs 4%, risk ratio [RR] = 0.58, P = .005), including lower rates of gastrointestinal cancers (RR = 0.34, P = .05) and all skin cancers (RR = 0.53, P = .05).

There were 18 deaths in the anastrozole group and 17 in the placebo group, including 2 vs 0 from breast cancer, 7 vs 10 from other cancers, 2 vs 2 from cerebrovascular accident or stroke, 3 vs 1 from cardiac arrest, and 4 vs 4 from other causes (P = .836 for differences in specific causes).  

Adverse Events

There was no difference between the anastrozole and placebo groups in frequency of fractures overall (9% and 8%) or by specific sites. Similarly, there was no difference between groups in frequency of thromboembolic events (1% and 1%), cerebrovascular events (< 1% and < 1%), or myocardial infarction/cardiac failure (< 1% and < 1%).

Musculoskeletal adverse events (64% vs 58%, RR = 1.10, P = .0001), including arthralgia (51% vs 46%, RR = 1.10, 95% confidence interval [CI] = 1.03–1.18), carpal tunnel syndrome (3% vs 2%, RR = 1.58, 95% CI = 1.08–2.30), and joint stiffness (7% vs 5%, RR = 1.51, 95% CI = 1.17–1.94), vasomotor symptoms (57% vs 49%, RR = 1.15, P < .0001), dry eyes (4% vs 2%, RR = 1.45, 95% CI = 1.04–2.01), and hypertension (5% vs 3%, RR = 1.64, 95% CI = 1.18–2.28) were significantly more common with anastrozole. Vaginal or uterine prolapse (1% vs 2%, RR = 0.42, 95% CI = 0.22–0.81) was significantly less common with anastrozole.

The investigators concluded, “Anastrozole effectively reduces incidence of breast cancer in high-risk postmenopausal women. This finding, along with the fact that most of the side-effects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer.”

Jack Cuzick, PhD, of Queen Mary University of London, is the corresponding author for the The Lancet article.

The study was funded by Cancer Research UK, National Health and Medical Research Council Australia, Sanofi-Aventis, and AstraZeneca. For full disclosures of the study authors visit www.thelancet.com.

MAMMOGRAPHY SCREENING?-NOT SO SIMPLE

A woman's decision to undergo mammography "should be individualized based on patients' risk profiles and preferences," concludes a systematic review of 50 years of breast cancer screening data, published in the April issue of JAMA.

How to best go about achieving that individualization is not entirely clear, but clinicians need to make an effort with the tools that are currently available, such as decision aids and risk models, suggest Lydia Pace, MD, MPH, and Nancy Keating, MD, MPH, both from Brigham and Women's Hospital in Boston, in their review.

The pair evaluated nearly 450 scientific articles from 1960 to 2014 for "evidence on the mortality benefit and chief harms of mammography screening."

After pouring over clinical trials, systematic reviews, meta-analyses, and observational studies, they conclude that the mortality benefit of mammography is "modest" and the risks of harm from screening are "significant."

This mix means that clinicians "must focus on promoting informed screening decisions," they write.

"There is a challenge for physicians to find the time to talk about this with patients," acknowledged Dr. Keating in an email toMedscape Medical News. "I do hope that the increasing availability of decision aids will make these discussions easier."

In an accompanying editorial, another pair of experts echo the main messages of the review.

"Balanced messaging is essential to help each woman make her own individual decision regarding her participation in screening mammography," write Joann Elmore, MD, MPH, from the University of Washington in Seattle, and Barnett Kramer, MD, MPH, from the National Cancer Institute in Bethesda, Maryland.

Discussions about screening "should begin with information about the woman's realistic risk of a breast cancer diagnosis," they add.

However, like Drs. Pace and Keating, the editorialists suggest there is a bit of a glitch in doing this. "The current ability to estimate individual risk is imprecise," they note.

The benefit of mammography is "less than once hoped" and the potential harms are "greater than anticipated," the editorialists write. "Yet that nuanced balance is not easily communicated."

In short, clinicians face a tremendous task when trying to communicate the risks and benefits of mammography screening to individual patients, they suggest.

They do offer some advice for clinicians who sit and talk with women considering screening: "Messages based on fear or guilt may impede full understanding."

Fifty Years of Data

In their review of 50 years of data, Drs. Pace and Keating conclude that mammography screening is associated with a 19% overall reduction of breast cancer mortality (approximately 15% for women in their 40s and 32% for women in their 60s).

But, for a 40- or 50-year-old woman undergoing 10 years of annual mammograms, the cumulative risk of a false-positive result is about 61%.

Additionally, about 19% of the cancers diagnosed during that 10-year period of mammograms would not have become clinically apparent without screening (and thus represent overdiagnosis). However, Drs. Pace and Keating note that "there is uncertainty about this [overdiagnosis] estimate."

Strong Response From Imaging Societies

The analysis from Drs. Pace and Keating met with fierce opposition from 2 medical societies: the American College of Radiology (ACR) and the Society of Breast Imaging (SBI).

In a joint press release, the 2 groups raise the specter of missed cancers and subsequent deaths.

"Breast cancer screening based primarily on risk — as discussed in the JAMA article — would miss the overwhelming majority of breast cancers present in women and result in thousands of unnecessary deaths each year," the statement reads.

Part of the problem with the study is that it relied too much on old data, the groups assert.

"The JAMA article authors also placed too much emphasis on the obsolete and low lifesaving benefit of mammography claimed in outdated or discredited studies," they state.

As an example, the critics cite the Canadian National Breast Screening Study (CNBSS), which is included in the JAMA analysis. CNBSS has been "widely discredited," and the World Health Organization officially excluded it from their analyses of screening's mortality benefit, according to the ACR/SBI statement.

"More recent" randomized controlled studies, say the 2 societies, "have reconfirmed that regular mammography screening cuts breast cancer deaths by roughly a third," which is about double that claimed by Drs. Pace and Keating, in all women 40 years and older — including women 40 to 49 years. This statement refers to Swedish studies from Hellquist et al andTabár et al, which are, respectively, the largest and longest running randomized trials, the ACR/SBI statement reports.

Dr. Keating countered this criticism. "Selectively reporting results only from the studies that showed the biggest benefits of mammography does not accurately reflect the larger body of research on screening mammography."

However, she conceded that their clinical sources were not perfect. "We agree that there are some limitations to all of the randomized trials of screening."

Nonetheless, in total, the trials cited in the analysis "offer the best data that we have," she added.

Tools at Hand: Decision Aids and Risk Models

Drs. Pace and Keating believe "more research" is needed to "optimize" the 2 primary tools for individualizing screening advice and education to patients: risk models and decision aids. But in the meantime, clinicians have to work with these instruments.

In a section of their review entitled "Individualizing Mammography Screening Decisions," they take a detailed look at both tools.

But first, they set the stage with some grounding statistics.

For a woman in the United States, "the average lifetime risk of breast cancer is about 12.3%; the 10-year risks of invasive breast cancer at ages 40, 50, and 60 years are 1.5%, 2.3%, and 3.5% respectively," they report.

Numerous risk factors have been identified for breast cancer, but "up to 60% of breast cancers occur in the absence of known risk factors," they note.

Nevertheless, attempting to establish a woman's individual risk is important. "The net benefit of screening depends greatly on baseline breast cancer risk, which should be incorporated into screening decisions," Drs. Pace and Keating write.

The Gail model is commonly used in clinical practice to assess a patient's risk. The risk factors incorporated into this model include age at menarche, age at first birth, number of first-degree relatives with breast cancer, number of previous breast biopsies, presence of atypical hyperplasia, and breast density.

But the Gail model and other patient risk models have an underlying fault. Drs. Pace and Keating note that they are "more accurate in predicting incidence in population subgroups and far less useful in identifying which individual women will or will not get cancer."

Nevertheless, they point out that the Gail model has been validated in 3 large populations and is the basis for the National Cancer Institute's online Breast Cancer Risk Assessment Tool.

Informed decisions about mammography screening should include consideration of "patients' values," they note, because these help reconcile information about the risks and benefits of screening.

"Decision aids using pamphlets, videos, or Internet tools can provide information, elicit preferences, and help patients make decisions," they write.

Numerous studies have consistently reported that decision aids provide benefits for patients, including an increased understanding of risks and benefits. However, 3 of the studies showed that the use of decision aids resulted in women having "decreased intentions to be screened," add Drs. Pace and Keating.

"Ideally, patients will be able to use a decision aid before they come to see a physician, and then can discuss what they learned with the physician at the visit," said Dr. Keating.

Dr. Pace's work for this review was funded by the Global Women's Health Fellowship at Brigham and Women's Hospital. Dr. Keating reports receiving research funding from the National Cancer Institute, the American Cancer Society, and the Komen for the Cure Foundation. Dr. Elmore reports serving as medical editor for the Informed Medical Decisions Foundation. Dr. Kramer has disclosed no relevant financial relationships.

JAMA. 2014;311:1298-1299, 1327-1335. Editorial, Abstract

FOLFOX FOR ESOPHAGEAL CHEMORADIOTHERAPY

In patients with inoperable esophageal cancer, definitive chemoradiotherapy offers a curative treatment option. A trial comparing 2 different regimens for the chemotherapy component of this treatment found that there was no significant difference in survival, but found other reasons to favor one of the regimens over the other.

Definitive chemoradiotherapy using fluorouracil plus leucovorin and oxaliplatin (FOLFOX) is an easier, less toxic, and cheaper option than chemoradiotherapy with fluorouracil and cisplatin, the researchers note.

The results come from the phase 2/3 PRODIGE5/ACCORD17 trial, published in the March issue of the Lancet Oncology.

"FOLFOX with radiotherapy is a convenient choice for patients for whom a nonoperative approach is selected," said first author Thierry Conroy, MD, chief executive officer at the Institut de Cancérologie de Lorraine in Vandoeuvre-lès-Nancy, France.

"Not only is it more convenient than fluorouracil and cisplatin, the FOLFOX regimen reduces some toxicities, such as mucositis, alopecia, and renal insufficiency, and lowers the risk of toxic deaths," Dr. Conroy told Medscape Medical News.

Another advantage of the FOLFOX regimen is that it can be administered in the outpatient setting, he noted.

In an accompanying comment, Bryan Burmeister, MD, from Princess Alexandra Hospital in Brisbane, Australia, writes that even though the study did not show an improvement in progression-free survival, it has "potentially shown an improvement in the therapeutic ratio by increasing the treatment options for cisplatin-intolerant patients, and reducing the burden of treatment cost through a less time-consuming and easier to administer regimen — and thus, potentially, improving quality of life for patients."

Comparing the 2 Regimens

Dr. Conroy and his group sought to determine whether progression-free survival in patients with nonoperable localized esophageal cancer could be improved by replacing cisplatin with FOLFOX in the standard chemotherapy regimen.

The open-label parallel-group trial involved patients 18 years and older treated at 1 of 24 centers in France from October 2004 to August 2011.

All had previously untreated stage I to IVA squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the esophagus. They were deemed unsuitable for surgery if they had disease that was potentially nonresectable, comorbidities that precluded surgery, or chose not to have surgery.

In the study cohort, Eastern Cooperative Oncology Group (ECOG) status ranged from 0 to 2, and all patients had sufficient caloric intake and adequate hematologic, renal, and hepatic function.

Patients were randomly assigned to 1 of 2 treatments: the FOLFOX regimen consisted of 134 patients in the intent-to-treat population and 131 patients in the safety population; the fluorouracil plus cisplatin regimen consisted of 133 patients in the intent-to-treat population and 128 patients in the safety population.

The safety population actually received the study drugs.

The FOLFOX regimen involved 6 cycles of oxaliplatin 85 mg/m², leucovorin 200 mg/m², bolus fluorouracil 400 mg/m², and infusional fluorouracil 1600 mg/m², delivered over 46 hours. The first 3 cycles were given concurrently with radiotherapy.

The fluorouracil plus cisplatin regimen involved 4 cycles of fluorouracil 1000 mg/m² per day for 4 days and cisplatin 75 mg/m² on day 1. Two of the cycles were given concurrently with radiotherapy.

All patients received 50 Gy radiotherapy delivered in 25 fractions (5 fractions per week).

The patients were followed for a median of 25.3 months.

There was no significant difference in median progression-free survival with the FOLFOX and fluorouracil plus cisplatin regimens (9.7 vs 9.4 months; P = .64). There was also no significant difference in median overall survival (20.2 vs 17.5 months; P = .70).

More Toxic Deaths With Fluorouracil Plus Cisplatin

However, there was a significant difference in the number of toxic deaths between the FOLFOX and fluorouracil plus cisplatin regimens (1 vs 6; P = .066).

Rates of grade 3/4 adverse events were not significantly different with the FOLFOX and fluorouracil plus cisplatin regimens. However, paraesthesia (47% vs 2%), sensory neuropathy (18% vs 1%), elevated aspartate aminotransferase concentrations (11% vs 2%), and elevated alanine aminotransferase concentrations (8% vs 2%) were more common with FOLFOX, and serum creatinine increases (3% vs 12%), mucositis (27% vs 32%), and alopecia (2% vs 9%) were more common with fluorouracil plus cisplatin.

"No difference in efficacy outcomes was noted for patients receiving chemoradiotherapy with FOLFOX and those receiving it with fluorouracil and cisplatin," Dr. Conroy reported.

However, "our data suggest that the FOLFOX regimen might be an alternative to the fluorouracil and cisplatin combination with concurrent radiotherapy in patients with localized esophageal cancer, because FOLFOX might be easier and more convenient to administer than the fluorouracil and cisplatin regimen. We feel that chemoradiotherapy including FOLFOX could therefore be used safely as an alternative treatment in this setting," he added.

Unsurprising Result

Because only 259 patients actually received the study drugs, the trial was underpowered, and the fact that there was no significant difference in progression-free survival was not surprising, Dr. Burmeister notes in his comment.

There were also no significant differences between the regimens for overall survival, proportion of endoscopic complete response, time to treatment failure, and occurrence of grade 3/4 toxic events, he points out.

In the past, patients who were cisplatin-intolerant have been treated with radiotherapy alone or with combinations of radiotherapy and nonplatinum-containing regimens, but most of these treatments have worse survival outcomes than standard chemotherapy, Dr. Burmeister writes.

In addition, high inpatient and outpatient admission rates are linked to cisplatin because of dehydration, meaning that there is a potential cost benefit to not including cisplatin in a treatment regimen.

"I commend the authors for completing this multicenter trial given its implications for the future management strategies for esophageal cancer," Dr. Burmeister concludes.

"It sets the scene for further randomized trials designed to test similar end points with other treatment regimens that contain platinum, such as a regimen of carboplatin, paclitaxel, and radiotherapy, which has been effective in the neoadjuvant treatment of operable esophageal carcinoma, and has low toxicity," he adds.

He urges the authors to publish their quality-of-life data. "A study of this type would be more complete with this additional data, which could enhance the argument for replacement of cisplatin with oxaliplatin."

The study was funded by UNICANCER, the French Health Ministry, sanofi-aventis, and the National League Against Cancer. Dr. Conroy reports receiving honoraria from sanofi-aventis. Dr. Burmeister has disclosed no relevant financial relationships.

Lancet Oncol. 2014;15:248-249, 305-314. Comment, Abstract

DEFIBROTIDE APPROVED FOR VOD

The first-in-class drug defibrotide (Defitelio, Gentium S.p.A., acquired by Jazz Pharmaceuticals in early 2014) was launched in Europe this week for use in the treatment of severe veno-occlusive disease (VOD), a life-threatening complication that can occur after hematopoietic stem cell transplantation (HSCT).

The drug was approved by the European Medicines Agency (EMA) in October 2013 for the treatment of severe VOD. It wasrecommended for approval in July 2013 after a resubmission and re-evaluation of the data.

In March 2013, an application for defibrotide for both the prevention and treatment of VOD was not recommended for approval. The company then removed the prevention part of the application, leaving the narrow indication of severe VOD, which is considered to be an unaddressed medical need.

In the United States, a registration file is in the process of being submitted to the US Food and Drug Administration (FDA).

Defibrotide, an oligonucleotide that acts as a polydeoxyribonucleotide adenosine receptor, has demonstrated antithrombotic, anti-inflammatory, and anti-ischemic properties.

The phase 3 registration data that formed the basis of the EMA approval showed a significant improvement in survival in patients with severe VOD, compared with historical control subjects. Those data, which will likely be submitted for publication in the near future, were originally discussed at the 2013 annual meeting of the European Society for Blood and Marrow Transplant (EBMT).

Phase 3 Registration Trial Results

The multicenter international registration trial was based at the Dana-Farber Cancer Institute in Boston, with participating sites across North America and in Israel, and was sponsored by Gentium S.p.A.

In the study, 102 patients with severe VOD were treated with defibrotide 25 mg/kg per day for a median of 22 days. Four doses were administered intravenously every 6 hours.

Those patients were compared with 32 patients who made up the historic control group.

"The risk characteristics of patients participating in this trial included advanced multiorgan failure. The patients were, by design, the severest in all of the trials that we have done with defibrotide to date," explained principal investigator Paul Richardson, MD, professor of medicine at Harvard Medical School in Cambridge, Massachusetts. "They were very sick patients with an otherwise dismal prognosis, including a mortality expected to be in excess of 80%," he told Medscape Medical News in an interview.

Survival 100 days after HSCT was 52% better in the defibrotide group than in the control group (38% vs 25%; P < .05). Specifically, more patients in the defibrotide group achieved a complete response 100 days after HSCT (24% vs 9%).

Hemorrhagic adverse events were similar in the defibrotide and control groups (65% vs 69%). In the defibrotide group, 18% of patients experienced a drug-related toxicity that led to discontinuation; otherwise, defibrotide was generally well tolerated.

"There was a significant difference in response rate and a significant difference in survival in favor of the defibrotide-treated patients," Dr. Richardson reported. "Importantly, the novel historic control methodology used was validated by other independent registry data showing that the historic controls were consistently reflective of what happens if severe VOD is left untreated, in both the published literature and from at least 2 major databases."

"Based on the validation of the historic controls, we feel comfortable that these data are reflective of clinical benefit," said Dr. Richardson.

He added that the data are further supported by a landmark EBMT prospective randomized prevention trial, which showed the clinical benefit of defibrotide in more than 400 high-risk pediatric patients (Lancet.2012;379:1301-1309), as previously reported by Medscape Medical News.

Interim data from the Treatment of an Investigational New Drug Study — the largest prospective evaluation of defibrotide to date — were also discussed at the EBMT meeting.

Of the 470 patients with severe VOD, 425 had undergone HSCT. They received defibrotide 25 mg/kg per day for a minimum of 21 days.

Interim results show that survival 100 days after HSCT is 48%, and complete response is in excess of 30%. Both findings are highly consistent with previous studies, and much better than expected, Dr. Richardson noted

Modest Beginnings by a Lake in Northern Italy

The story of defibrotide began in 1995 in Como, Italy. In fact, as it has in some of medicine's greatest discoveries, serendipity played a hand in the discovery of defibrotide. "It dropped out of the production process of heparin, and the scientists at Crinos [as Gentium S.p.A. was then known] decided to take a closer look," Dr. Richardson explained.

Its development was based on a hypothesis first proposed by Dr. Richardson, and then embraced by the company. That led to the first data showing the clinical benefit of defibrotide in 19 patients with severe VOD treated on a compassionate basis (Blood. 1998;92:737-744).

Dr. Richardson's conviction in the product as a novel therapy for VOD was borne out of the frustration of seeing the adverse effects of the clot-busting therapies — heparin and tissue plasminogen activator (tPA) — used at the time.

The first and very compelling use of defibrotide was in a 28-year-old patient of Dr. Richardson with relapsed Hodgkin's disease who was undergoing stem cell transplantation with curative intent. After HSCT, she developed the life-threatening complication of VOD related to the conditioning treatment that affects the microvessels of the liver, damaging the endothelial lining, leading to vascular occlusion and, ultimately, liver failure, and she experienced both kidney and pulmonary failure as well.

She was initially treated with heparin and tPA, which both failed and also caused bleeding. "We then abandoned those treatments and started defibrotide with an FDA authorization for compassionate use," reported Dr. Richardson. "What was so remarkable was that she tolerated the drug really well, had a dramatic reduction in her bilirubin level after 12 days of treatment, and had an improvement in her syndrome overall."

At the 12-day point — the standard cutoff for heparin and tPA — Dr. Richardson held treatment; she stabilized for 2 days but then significantly worsened. Treatment was restarted and she completed 4 weeks of therapy with defibrotide, achieving a complete response.

"Her bilirubin was initially 55 mg/dL and nobody expected her to survive," he explained, but she went on to do very well, with long-term survival.

This patient was 1 of the 19 reported in the first data. After that publication, larger clinical trials were conducted, including the phase 3 trial that was submitted for registration.

"It's taken a long time to get to where we are now," Dr. Richardson said. "It was a unique partnership with a small Italian pharmaceutical company that was willing to test this agent in such a difficult and challenging setting. Together, we [at Dana-Farber] built a foundation with various research grants for the project, and the company provided free drug, as well as supporting our determination to see this drug fulfill its potential for this life-threatening condition."

Reversal of the Physician–Company Relationship

The story of defibrotide turns the conventional concept of the pharmaceutical company–physician partnership on its head. Rather than having the pharmaceutical company vigorously promote a drug to the clinic, the doctors led the way. "We moved forward slowly because initially Gentium had only limited experience in developing new drugs and the field was incredibly complex, with no previous approvals in this setting, making this very much a learning experience for all of us," Dr. Richardson explained.

Defibrotide is a significant example of a progressive physician–pharma relationship, said Mohamad Mohty, MD, professor of hematology at Saint-Antoine Hospital and University Pierre & Marie Curie in Paris, and president-elect of the EBMT.

"This is a really a true model of how society can work hand in hand with pharmaceutical companies to develop effective products," said Dr. Mohty. "It's a crossfertilization, in that it allows us to let the company know what we need from a drug, and the company to let us know their needs from physicians. It can serve as a model to many other developments."

Dr. Richardson agrees that partnerships with pharma are a key way forward. "In reality, when we started the project years ago, it is reasonable to suggest that no mainstream pharmaceutical company would have so enthusiastically engaged in this type of problem, with such sick patients and in which attributable toxicities are very difficult to dissect," he said.

In fact, many leaders in the field have expressed their surprise at the development of defibrotide for severe VOD, acknowledging that this really is a place where even angels fear to tread, but applauded the achievement reflected by this unique approval.

"However, I truly believe that if you put the patient first and go from there, you usually won't go wrong," said Dr. Richardson, echoing a sentiment expressed by other clinicians at the meeting.

Defibrotide "has significantly improved patient outcomes in allogeneic and autologous transplants, and reduced the incidence of VOD," said Elaine Smyth, RGN, RSCN, nurse specialist in transplant at Our Lady's Children's Hospital in Crumlin, Dublin, who has used defibrotide under trial conditions for about 6 years. "Prior to this, children just received symptom management and still suffered terribly. Now we have reduced admissions to the ICU and hospital stays, with much better results overall."

For the continuing phase 3 study, Jazz Pharmaceuticals is collaborating with the EBMT to compile a registry of patients expected to undergo HSCT in the next 2 to 3 years.

An important part of the development of defibrotide is the support of the orphan products division of the FDA. A New Drug Application is currently being compiled, which the company hopes to have submitted and reviewed within the next year. In the absence of any approved treatments for VOD in the United States, defibrotide has been made available as an Investigational New Drug, through an expanded access treatment program, for patients with VOD.

Dr. Richardson reports serving on advisory committees for Gentium. Dr. Mohty reports receiving research support and honoraria from Gentium. Ms. Smyth has disclosed no relevant financial relationships.

NINTEDANIB FOR NSCLC

Geneva, Switzerland — A new oral angiogenesis inhibitor for the treatment of lung cancer could be edging closer to the market: Approval application for nintedanib (Boehringer Ingelheim) has been filed in Europe and is being prepared for the United States.

The data for nintedanib come from the phase 3 trial known as LUME-Lung-1, recently published in the Lancet Oncology(2014;15:143-155).

The data were also presented in a poster and discussed here at the European Lung Cancer Conference (ELCC) 2014 by principal investigator, Martin Reck, MD, PhD, head of thoracic oncology at the Lungen Clinic, Grosshansdorf, Germany.

The trial was conducted in 1314 previously treated patients with stage 3B or 4 or recurrent non-small cell lung cancer (NSCLC), who were given docetaxel as second-line therapy. Adding nintedanib significantly improved the progression-free survival to 3.4 months vs 2.7 months with docetaxel alone (hazard ratio [HR], 0.79; P = .0019).

The improvement in overall survival (OS) for all participants did not reach significance (10.1 vs 9.1 months; P = .27).

However, the survival difference was significant in 2 patient subgroups that were prespecified, Dr. Reck noted. The survival difference was significant in the subgroups of patients with adenocarcinoma histology (about half of all the participants)—12.6 vs 10.3 months (HR, 0.83; P = .0359)—and also in the subgroup of patients with adenocarcinoma and fast-growing tumors (who progressed within 9 months of starting therapy)—10.9 vs 7.9 months (HR, 0.75; P .0073).

Dr. Reck said that adenocarcinoma histology can act as a clinical biomarker for patients who are likely to benefit from this approach.

He noted that to date, no targeted agent has shown an improvement in survival when added to second-line chemotherapy in lung cancer.

Boehringer Ingelheim said that in its filing with the European regulatory authorities, it has specified use of nintedanib in adenocarcinoma NSCLC.

However, some lung cancer experts are not impressed by the data.

The improvement in progression-free survival (PFS) was only 0.7 month (about 3 weeks), which may be statistically significant but is not clinically significant, said Pasi Janne, MD, PhD, from the Dana Farber Cancer Center in Boston, Massachusetts, during a discussion of the poster presentation. He also emphasized that there was no OS difference in the overall intention-to-treat population, only in a subgroup of patients.

To Medscape Medical News, he commented that emphasizing the OS survival in a subgroup of the participants was "data dredging." He was skeptical over whether nintedanib would get approved, and noted that several previous oral angiogenesis inhibitors have been tested in lung cancer and failed, including vandetanib, sunitinib, and sorafenib.

The trial with vandetanib also included docetaxel in very similar patients (Lancet Oncol. 2010;11:619-626) and showed a "similarly not very impressive PFS improvement and no improvement in overall OS," he said.

In his discussion, Dr. Janne said, "One of the issues is that we have chemotherapy in both treatment arms, and unless the clinical effect is dramatic it's really hard to see an improvement."

Need for a Biomarker

It is not clear that it is worth pursuing this line of clinical development of oral angiogenesis inhibitors with chemotherapy in lung cancer in the absence of a biomarker, Dr. Janne said. "The angiogenesis field has been crying out for a biomarker for years, and yet there is nothing that has been clearly identified so far, and it is not clear in my mind that it is worth pursuing this strategy without some additional biology," he said.

A similar point was made by Roy Herbst, MD, PhD, Ensign professor of medicine and chief of medical oncology at the Yale Cancer Center, New Haven, Connecticut, who was approached for comment. "I would feel much more confident with this in future trials or in the clinic if there was a biomarker," he toldMedscape Medical News.

Dr. Herbst noted that the results were similar to those seen in the vandetanib trial (which he headed), but those data were not submitted for approval — a decision that he was not involved with, he noted — but he did say "we were looking for meaningful outcomes."

The nintedanib trial "was positive for PFS, although quite modestly, and it did meet a survival endpoint, albeit in a subgroup of patients, but that was prespecified," he said. "My feeling is that there is a signal here, but I would feel much better about it if we could find a biomarker to enhance this effect and bring the hazard ratio down to 7 or better."

"In the era of patient-tailored therapy, biomarkers are crucial to enrich the patient population that benefit and reduce the number of patients who have substantial adverse reactions with no improvement in the clinical outcome," Dr. Herbst wrote with coauthors in an editorial that accompanied the publication.

Adverse Effects Manageable

Dr. Reck reported that the adverse-effect profile of nintedanib was manageable. Adverse events that were more common in the nintedanib plus docetaxel group included diarrhea and transient elevation of liver enzymes. The incidence of bleeding events was low (with no severe pulmonary bleeding), as was the incidence of hypertensive events (with no severe hypertension), he said.

To Medscape Medical News, Dr. Reck commented that nintedanib appears to have a milder adverse-effect profile than that seen with bevacizumab (Avastin, Genentech), which to date is the only angiogenesis inhibitor approved for use in lung cancer, but in the first-line setting. In particular, "bleeding is not a problem" with nintedanib, he said, not even in patients with squamous histology, for whom bevacizumab is contraindicated because of the high risk for bleeding.

A second trial with nintedanib, known as LUME-Lung 2, was recently stopped early for "futility" after an interim analysis of the data, based on investigator review, suggested there would be no significant difference between the treatment groups: nintedanib with pemetrexed (Alimta, Lilly) vs pemetrexed alone. However, a later analysis, which was an independent review and included a few more events, did find a significant improvement in median PFS (4.4 vs 3.6 months; P = .0435), Dr. Reck said. Details of the LUME-Lung 2 trial were reported in a poster at the 2013 American Society of Clinical Oncology annual meeting.

These studies were funded by Boehringer Ingelheim, manufacturer of nintedanib, and several of the coauthors are company employees.

European Lung Cancer Conference (ELCC) 2014. Abstract 97PD. Presented March 28, 2014.

CHEMOTHERAPY ACCELERATES MOLECULAR AGING

Physicians have long suspected that chemotherapy can accelerate the aging process in patients treated for cancer. Using a test developed at UNC Lineberger Comprehensive Cancer Center to determine molecular aging, oncologists have directly measured the impact of anticancer chemotherapy drugs on biological aging. The study by Sanoff et al was published in the Journal of the National Cancer Institute.

Study Details

Researchers measured the level of p16, a protein that causes cellular aging, in the blood of 33 women over the age of 50 who had undergone chemotherapy for curable breast cancer. Samples were taken for analysis of molecular age from patients before chemotherapy, immediately following chemotherapy, and a year after therapy finished. The analysis showed that curative chemotherapy also caused an increase in a patient’s molecular age that on average was equivalent to 15 years of normal aging. The same was true in a separate group of 176 breast cancer survivors who had received chemotherapy on average 3.5 years prior.

Hanna Sanoff, MD, Assistant Professor at the UNC School of Medicine and member of UNC Lineberger said that the results indicate that the p16 test holds promise as a means of evaluating how chemotherapy will affect a patient’s long-term health and survival and as a predictive biomarker for the long-term toxicity of chemotherapy.

Role of p16

“Our theory is that if you have an advanced molecular age to begin with, it will be harder for you to tolerate chemotherapy,” said Dr. Sanoff. “We believe a high level of p16 before treatment could mean that a patient will have a harder time making new blood cells after each chemotherapy treatment, and therefore be at greater risk for anemia and infection during chemotherapy.”

The key role of p16 in human aging has been established over the last decade in the lab of Norman E. Sharpless, MD, Director of UNC Lineberger. Research conducted in Dr. Sharpless’ lab showed in 2004 that the levels of p16 increase exponentially with aging, and developed the p16 blood test for human use in 2009.

Next Steps

The next direction for this research, ongoing under the leadership of Hyman B. Muss, MD, Director of UNC Lineberger’s Geriatric Oncology Program, involves determining if markers of molecular age predict patients’ physical function and outcome in a number of clinical settings.

“While these findings are highly provocative, we have much more to study and will have to verify in future trials how these changes in molecular aging affect long term survival,” said Dr. Muss. “Adjuvant chemotherapy has dramatically improved breast cancer survival and pending further data, the results of our study should not effect adjuvant chemotherapy decisions.”

Drs. Muss and Sharpless are the corresponding authors for the Journal of the National Cancer Institutearticle.

This research was supported by grants from the National Institutes of Health, the Paul Glenn Foundation, the Burroughs Wellcome Fund, and the Breast Cancer Research Foundation. UNC holds a patent on the diagnostic test of molecular aging. The lead study authors reported no potential conflicts of interest.

UNRELIABILITY OF ERCC1 READOUTS

In the phase II Tailored Postsurgical Therapy in Early-Stage NSCLC (TASTE) trial (IFCT-0801), reported in theJournal of Clinical Oncology, Wislez et al examined the feasibility of customized adjuvant treatment based on EGFRmutation status and expression of ERCC1 (excision repair cross-complementation group 1), a predictor of cisplatin response, in patients with non–small cell lung cancer (NSCLC). Although the trial met its primary endpoint of ≥ 80% of patients being able to start adjuvant chemotherapy within 2 months of surgery, a phase III trial of the customized approach was cancelled due to unreliability of ERCC1 immunohistochemical readouts.

The relationship between ERCC1 expression and cisplatin resistance was confirmed by ERCC1 immunohistochemical analysis in NSCLC patients in the IALT (International Adjuvant Lung Cancer) trial, in which adjuvant therapy significantly prolonged survival of patients with ERCC1-negative tumors vs ERCC1-positive tumors compared with observation. Among patients not receiving adjuvant chemotherapy, survival was longer in those with ERCC1-positive vs ERCC1-negative tumors, suggesting that ERCC1-positive patients can be spared chemotherapy.

Study Details

In the study, 150 patients with completely resected nonsquamous cell stage II or IIIA non-N2 tumors were randomly assigned to four standard-dose courses of cisplatin plus pemetrexed (Alimta) (n = 74) or customized treatment (n = 76) consisting of erlotinib (Tarceva) at 150 mg/d for 1 year in patients with activated EGFR mutations, four courses of cisplatin/pemetrexed in ERCC1-negative patients, and follow-up in ERCC1-positive patients. The primary objective was to start adjuvant therapy by day 61 after surgery, with biomarker information being available no later than day 56.

Success Rate

All patients in the standard treatment group received cisplatin/pemetrexed. In the customized treatment group, 53 (70%) received cisplatin/pemetrexed, 7 (9%) received erlotinib, and 16 (21%) underwent follow-up. Among all patients, chemotherapy was initiated before day 61 with biomarker results available in 120 patients, yielding an overall success rate of 80%, including rates of 77% in the standard treatment group and 83% in the customized treatment group.

Discrepant ERCC1 Immunohistochemical Findings

However, the investigators observed that their ERCC1 immunohistochemical results significantly differed from those in the IALT analysis, with 25.3% of patients being ERCC1-positive in the current study compared with 44% in the IALT study. Restaining of the IALT samples with the 8F1 antibody commercially available in 2011 showed discrepancies between the ERCC1 [immunohistochemical] results obtained in IALT in 2006 and those obtained in the current study.

The investigators stated, “The current batches of the monoclonal antibody 8F1, as well as all other commercial antibodies, are unable to make the distinction between the four isoforms of the ERCC1 protein, whereas only one isoform has full capacities for nucleotide excision repair. The ERCC1 [immunohistochemical] readouts were thus found to be unexpectedly unreliable.” The phase III portion of the TASTE program was thus cancelled.

The investigators concluded, “The primary end point of the trial was met, demonstrating the feasibility of a national biology-driven trial in the adjuvant NSCLC setting. Nevertheless, the phase III part was canceled because of the unreliability of the ERCC1 immunohistochemical readouts.”

Marie Wislez, MD, PhD, of Assistance Publique des Hôpitaux de Paris, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by the French Cooperative Thoracic Intergroup, Institut National du Cancer bioTASTE grants, and grants from Eli Lilly and Roche. For full disclosures of the study authors, visitjco.ascopubs.org.